Abstract Th2 and Th17 are two major arms of adaptive immunity involved in protective and pathological responses. The range of their immune-mediated pathologies includes allergic diseases (Th2), Crohn?s disease (Th17), multiple sclerosis (Th17) and psoriasis (Th17). Despite the introduction of biologics such as anti-cytokines Abs, more effective and low-cost therapies are not yet available. We have identified a new pathway that regulates both Th2 and Th17 differentiation by cAMP levels in dendritic cells (DC). In this MPI RO1 application entitled: ?A novel pathway of Th17/Th2 induction - the role of cAMP signaling in DC? we propose that exploring the underlying mechanisms and signaling events mediated through the G proteins; G?s (Gnas) and G?i (Gnai2), which stimulate and inhibit cAMP synthesis, respectively, can provide the foundation for such new therapies. The inhibition of this pathway (low cAMP) provokes Th2-inducing DC (pro-Th2 DC), and its activation (high cAMP) induces Th17-inducing DC (pro-Th17 DC). We generated two genetic mouse models; Gnas?CD11c that develop spontaneous Th2 bias and Gnai2?CD11c that develop a Th17 bias responses. We recently identified that different cAMP inducers regulate the expression levels of transcription factors in cDC2 cells that provoke Th17/Th2 differentiation such as interferon regulatory factor 4 (IRF4), IRF5, Kruppel-like factor 4 (KLF4) and Notch2. Here we shown that different cAMP inducers regulate the expression levels of these factors and switch the subsequent Th bias, which has led us to propose that the cDC2 cells represent a plastic DC subpopulation and that the cAMP levels dictate whether the cDC2 have a pro-Th17 and pro-Th2 bias. Hence, in this application we will explore and dissect the following topics: In SA1 - we will analyze whether increasing cAMP by genetic deletion of Gnai2 in DC causes a Th17-associated immunopathology overtime, in SA2 ? we will determine and test the transcriptional network that defines the phenotypic pro-Th17 or pro-Th2 cDC2 subpopulations, in SA3 - we will test whether GPCR agonists (i.e., ?2AR agonists) that increase cAMP levels, provoke Th17-driven neutrophilic asthma, and in SA4 - we will identify and functionally test novel pro-Th17 or pro-Th2 mediators produced by DC cells. In summary - our discovery that cAMP regulates the pro-Th2 and pro-Th17 inducing properties of cDCs has led to the identification of new pathway of Th2/Th17 regulation. The results will provide new insights into the plasticity of cDC2 and Th2- and Th17- biasing. It has the potential to advance basic immunological research and establish the basis for novel and innovative immunotherapeutic strategies.